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Biomedical subjects

A Weber

Publications and source records attributed to A Weber.

At least 73 records · Page 4Linked to original sources
PubMed2002

Carcinogen-induced site-specific mutagenesis and genetic susceptibility in squamous cell carcinoma of the head and neck.

Tobacco and alcohol have been identified as the most important risk factors for squamous cell carcinomas of the head and neck (HNSCC). Especially for tobacco, some of the carcinogen-induced mutations that trigger transformation have been identified. Much attempt has been made to show a relationship between the mutations of growth regulatory genes, i.e. tumor suppressor- or oncogenes, and the exposure to specific exogeneous mutagens. One of the best examined genes - harboring the most DNA damages (DNA adducts) - caused by xenobiotics is p53. This tumor suppressor gene is an important regulator of cell cycle and apoptosis and is mutated in 40-60% of all HNSCC. Further studies link specific mutations of the ras oncogene to definite carcinogens. The question of why these mutations lead to cancer in some smokers but not in others, i.e. the individual's susceptibility to external carcinogens, remains unclear. One possibility is the individual's ability (or non-ability) of detoxifying carcinogenic xenobiotics or repairing the DNA damages they caused. There are several known polymorphisms of enzymes involved in detoxification as well as in DNA repair - which might explain the interindividual variable susceptibility to HNSCC in smokers and drinkers. However, the results of several examined polymorphisms are diverse or even controversial. The diversity might be due to ethnical differences, study populations, tumor localizations as well as intratumoral heterogeneity. In this review, we attempt to discuss the carcinogen-specific mutations as well as the genetic polymorphisms, which may transfer an enhanced susceptibility to suffer HNSCC.

Alcohol Drinking↗
PubMed2002

The Azoospermia region AZFa: an evolutionar y view.

Compared to other regions on the human Y chromosome, the genomic segment encompassing the functionally defined AZFa locus has undergone higher X-Y sequence divergence, which is detectable by fluorescence in-situ hybridisation. This allows an evolutionary definition of an interval enclosing AZFa with a size of about 1.1 Mb. The region includes the genes USP9Y, DBY and UTY and is limited by evolutionary breakpoints within the PAC clones 41L06 and 46M11. These breakpoints restrict an area of possible male specific evolution that may have resulted in the acquisition of male specific functions, including a role in spermatogenesis.

Cells, Cultured↗
PubMed2001

Two-dimensional gas chromatography and trilinear partial least squares for the quantitative analysis of aromatic and naphthene content in naphtha.

Quantitative analysis of naphtha samples is demonstrated using comprehensive two-dimensional gas chromatography (GC x GC) and chemometrics. This work is aimed at providing a GC system for the quantitative and qualitative analysis of complex process streams for process monitoring and control. The high-speed GC x GC analysis of naphtha is accomplished through short GC columns, high carrier gas velocities, and partial chromatographic peak resolution followed by multivariate quantitative analysis. Six min GC x GC separations are analyzed with trilinear partial least squares (tri-PLS) to predict the aromatic and naphthene (cycloalkanes) content of naphtha samples. The 6-min GC x GC separation time is over 16 times faster than a single-GC-column standard method in which a single-column separation resolves the aromatic and naphthene compounds in naphtha and predicts the aromatic and naphthene percent concentrations through addition of the resolved signals. Acceptable quantitative precision is provided by GC x GC/tri-PLS.

Journal Article↗
PubMed2001

Transplantation of hepatocytes in nonhuman primates: a preclinical model for the treatment of hepatic metabolic diseases.

BACKGROUND: The transplantation of isolated hepatocytes in large animals, including nonhuman primates, must be evaluated before clinical trials are performed. However, in the absence of large transgenic animals and large-animal (as opposed to small-animal) models of genetic deficiencies, it is difficult to evaluate the fate of transplanted hepatocytes, their localization, survival, and function within the parenchyma of the host liver. In this work, we aimed to develop a technique for delivering hepatocytes to the liver of a nonhuman primate and to evaluate their localization and functionality in the short term. METHODS: A 20% hepatectomy was performed in 34 cynomolgus monkeys (Macaca fascicularis) and hepatocytes were isolated. Hepatocytes were labeled in vitro with a recombinant retrovirus expressing the beta-galactosidase gene and returned to the liver by infusion through a portal catheter left in place. Liver biopsies were performed 4 and 7 d after transplantation. RESULTS: Twenty-four monkeys underwent surgery to define the necessary technical adjustments and to optimize conditions. Six monkeys died. The whole protocol, including the transplantation of genetically marked hepatocytes and procurement of liver biopsies, was performed in the remaining 10 monkeys. In eight monkeys, transplanted hepatocytes expressing the beta-galactosidase gene were widely distributed in the portal tracts, sinusoids, and hepatocyte plates of the host liver 4 and 7 d after transplantation. CONCLUSIONS: We have developed an experimental nonhuman primate model for the evaluation of hepatocyte transplantation. We demonstrated the engraftment and functioning of transplanted hepatocytes in the host liver 4 and 7 d after transplantation.

Animals↗
PubMed2001

[Interdisciplinary management of chronic tinnitus (II)].

Tinnitus is defined as the perception of sound in the absence of any appropriate external stimulation. It is a common, bothersome and hard-to-evaluate symptom and in most cases it cannot be objectified. Its incidence in Germany and the western world is about 10%. About 1-2% of the population are severely disturbed by tinnitus and it may disrupt everyday activities and sleep. Recent theoretical developments favour a neurophysiological approach as an explanation for tinnitus in addition to a psychoacoustic model based on peripheral lesion in the cochlea or auditory nerve. In the neurophysiological model, the processing of the tinnitus signal plays a dominant role in its detection, perception and evaluation. Therefore, attention and other psychological factors become important in the understanding and treatment of tinnitus. Many treatments of chronic tinnitus have been proposed and implemented. Today, cognitive-behavioural treatment is regarded as an important part of an integrative therapy which may be compiled of counselling, relaxation therapy, instrumental (hearing aid, tinnitus masker, tinnitus instrument, tinnitus noiser) and pharmacological tools (lidocaine, neurotransmitters). In well-controlled studies the empirical support for other therapeutical approaches such as acupuncture is weak. This work gives a review of the current knowledge of the etiology, pathogenesis, epidemiology, the interdisciplinary diagnostic approach and treatment of tinnitus and especially focuses on insurance and medico-legal aspects.

Chronic Disease↗
PubMed2001

Expression of P27(KIP1) is prognostic and independent of MYCN amplification in human neuroblastoma.

Amplification of the MYCN gene is significantly associated with an unfavorable prognosis and rapid progression in human neuroblastoma tumors. One potential mechanism by which MYCN may cause these effects is by deregulating cell proliferation. Tissue culture experiments support a model in which MYC genes stimulate cell cycle progression by antagonizing the function of the cell cycle inhibitor p27(kip1). In culture, activation of MYC induces both sequestration of p27(kip1) by cyclin D complexes and its subsequent proteolytic degradation. We have tested whether this model applies to human neuroblastoma in a retrospective study of 100 primary tumor biopsy samples from neuroblastoma patients with a documented follow-up. Consistent with this hypothesis, MYCN-amplified tumors express high levels of both cyclin A and proliferating cell nuclear antigen, 2 marker proteins of cell proliferation. Further, expression levels of p27(kip1) are of prognostic significance in human neuroblastoma patients. Similar to tissue culture systems, p27(kip1) is sequestered by cyclin D complexes in a subset of human neuroblastoma samples. Surprisingly, however, expression levels of p27(kip1) are prognostic independent of MYCN amplification, and tumors that have an amplified MYCN gene do not express elevated levels of D-type cyclins or contain significantly lower levels of p27(kip1). Our data do not support a model in which regulation of p27(kip1) function is an important mechanism by which amplified MYCN deregulates cell proliferation in neuroblastoma.

Biomarkers, Tumor↗
PubMed2001

Cystic fibrosis pathogens activate Ca2+-dependent mitogen-activated protein kinase signaling pathways in airway epithelial cells.

Much of the pulmonary disease in cystic fibrosis is associated with polymorphonuclear leukocyte-dominated airway inflammation caused by bacterial infection. Respiratory epithelial cells express the polymorphonuclear chemokine interleukin-8 (IL-8) in response to ligation of asialylated glycolipid receptors, which are increased on damaged or regenerating cells and those with cystic fibrosis transmembrane conductance regulator mutations. Because both Pseudomonas aeruginosa and Staphylococcus aureus, the most common pathogens in cystic fibrosis, bind asialylated glycolipid receptors such as asialoGM1, we postulated that diverse bacteria can activate a common epithelial signaling pathway to elicit IL-8 expression. P. aeruginosa PAO1 but not pil mutants and S. aureus RN6390 but not the agr mutant RN6911 stimulated increases in [Ca(2+)](i) in 1HAEo- airway epithelial cells. This response stimulated p38 and ERK1/2 mitogen-activated protein kinase (MAPK) signaling cascades resulting in NF-kappaB activation and IL-8 expression. Ligation of the asialoGM1 receptor or thapsigargin-elicited Ca(2+) release activated this pathway, whereas P. aeruginosa lipopolysaccharide did not. The rapid kinetics of epithelial activation precluded bacterial invasion of the epithelium. Recognition of asialylated glycolipid receptors on airway epithelial cells provides a common pathway for Gram-positive and Gram-negative organisms to initiate an epithelial inflammatory response.

Adhesins, Bacterial↗
PubMed2001

Synthesis of the Streptomyces lividans maltodextrin ABC transporter depends on the presence of the regulator MalR.

During growth with maltotriose or amylose, Streptomyces lividans and Streptomyces coelicolor A3(2) synthesize a maltodextrin uptake system with highest specificity for maltotriose. The transport activity is absent in mutants of S. coelicolor A3(2) lacking a functional MalE binding protein. Cloning and sequencing data suggest that the mal operon of S. coelicolor A3(2) corresponds to the one of S. lividans and that the deduced S. lividans Reg1 amino acid sequence is identical to that of MalR from S. coelicolor A3(2). It can be concluded that both strains have the same ABC transport system for maltodextrins. The S. lividans malR was cloned in Escherichia coli in frame with six histidine-encoding codons. The resulting, purified 6HisMalR(SI) was shown to bind to two motifs within the S. lividans malR-malE intergenic region and to dissociate in the presence of maltopentaose.

ATP-Binding Cassette Transporters↗
PubMed2001

Pseudomonas aeruginosa infection of respiratory epithelium in a cystic fibrosis xenograft model.

Pulmonary infection with Pseudomonas aeruginosa in patients with cystic fibrosis (CF) causes a chronic destructive bronchitis. A xenograft model was used to study the susceptibility of the CF respiratory epithelium to P. aeruginosa strain PAK and the virulence of certain mutants. Despite an early trend toward increased susceptibility, colonization of CF xenografts (ID(95), 62 colony-forming units [cfu]) was not statistically different (P=.5) than in xenografts with normal respiratory cells (ID(95), 1.2x10(3) cfu). Infection severity in 12 CF xenografts (mean polymorphonuclear leukocyte [PMNL] density, 1.88x10(6)+/-1.75x10(6)/xenograft) was similar to that in 16 non-CF xenografts (3.19x10(6)+/-2.45x10(6) PMNL/xenograft; P=.38), despite slightly greater bacterial density in the CF xenografts (mean, 1.57+/-2.73x10(6) cfu/xenograft) versus xenografts with normal epithelium (mean, 1.03+/-1.3x10(6) cfu/xenograft). P. aeruginosa mutants pilA and fliF, but not rpoN, colonized normal respiratory xenografts, indicating that colonization and infection in this model depend on an uncharacterized RpoN-controlled gene. This model appears to be suitable for genetic study of P. aeruginosa virulence but not of the CF respiratory tract's unique susceptibility.

Animals↗
PubMed2001

Defective interplay of activators and repressors with TFIH in xeroderma pigmentosum.

Inherited mutations of the TFIIH helicase subunits xeroderma pigmentosum (XP) B or XPD yield overlapping DNA repair and transcription syndromes. The high risk of cancer in these patients is not fully explained by the repair defect. The transcription defect is subtle and has proven more difficult to evaluate. Here, XPB and XPD mutations are shown to block transcription activation by the FUSE Binding Protein (FBP), a regulator of c-myc expression, and repression by the FBP Interacting Repressor (FIR). Through TFIIH, FBP facilitates transcription until promoter escape, whereas after initiation, FIR uses TFIIH to delay promoter escape. Mutations in TFIIH that impair regulation by FBP and FIR affect proper regulation of c-myc expression and have implications in the development of malignancy.

Blotting, Western↗
PubMed2001

Engraftment of autologous retrovirally transduced hepatocytes after intraportal transplantation into nonhuman primates: implication for ex vivo gene therapy.

The main impediment to effective ex vivo liver gene therapy of metabolic diseases is the lack of experimental work on large animals to resolve such important issues as effective gene delivery, cell-processing techniques, and the development of appropriate vectors. We have used a nonhuman primate, as a preclinical model, to analyze the limiting steps of this approach using recombinant retroviruses. Seven monkeys (Macaca fascicularis) underwent the complete protocol: their left liver lobe was resected, a catheter was placed in the inferior mesenteric vein and connected to an infusion chamber, and the hepatocytes were isolated, cultured, and transduced with a retroviral vector containing the beta-galactosidase gene. The hepatocytes were harvested and returned to the host via the infusion chamber. Biopsies were taken 4-40 days later. No animal was killed in the course of the experiments. They all tolerated the procedure well. We have developed and defined conditions that permit the proliferation and transduction of up to 90% of the plated hepatocytes. A significant proportion of genetically modified cells, representing up to 3% of the liver mass, were safely delivered to the liver via the chamber. Polymerase chain reaction analysis detected integrated viral DNA sequences and quantitative analysis of the in situ beta-Gal-expressing hepatocytes indicated that a significant amount of transduced hepatocytes, up to 2%, had become integrated into the liver and were functional. These results represent substantial advances in the development of the ex vivo approach and suggest that this approach is of clinical relevance for liver-directed gene therapy.

Animals↗
PubMed2001

Acute phase proteins in serum and milk from dairy cows with clinical mastitis.

The serum concentrations of haptoglobin, serum amyloid A and alpha1 acid glycoprotein were determined in serum collected from healthy dairy cows and cows with clinical mastitis, graded as mild (clots in milk) or moderate (clots in milk and visible signs of inflammation in the mammary gland/s) to assess their relative diagnostic value in detecting the disease. The concentrations of haptoglobin and serum amyloid A were also measured in milk collected from infected and uninfected quarters. The concentrations of haptoglobin and serum amyloid A were higher in the serum and milk from the cows with mild or moderate mastitis. The diagnostic value of haptoglobin in differentiating between healthy animals and those with mastitis gave sensitivities and specificities of 82 per cent and 94 per cent respectively with serum and 86 per cent and 100 per cent with milk. The diagnostic value of serum amyloid A in differentiating between healthy animals and those with mastitis gave sensitivities and specificities of 83 per cent and 90 per cent with serum and 93 per cent and 100 per cent with milk. The diagnostic value of serum alpha1 acid glycoprotein in differentiating between healthy animals and those with mastitis gave sensitivities and specificities of 62 per cent and 91 per cent.

Acute Disease↗
PubMed2001

CYP3A inductive potential of the rifamycins, rifabutin and rifampin, in the rabbit.

Rifabutin is effective in the treatment and prevention of Mycobacterium avium infection in people with HIV infection. Rifabutin is structurally related to another rifamycin, rifampin, a well-known inducer of the human P-450 isoform 3A. The rabbit isoform CYP3A6 and the human isoform CYP3A4 have similar P-450 predominance and substrate specificity and are both induced by rifampin. Our goal was to predict the CYP3A induction capacity of rifabutin and to determine if ex vivo CYP3A induction potential of rifamycins is predictive of that obtained in vivo. We determined the in vivo and ex vivo CYP3A6 induction by 4 days of treatment with rifabutin (100 mg/kg), rifampin (100 mg/kg), or vehicle (DMSO) in the rabbit. The ex vivo measures were CYP3A6 activity (N-demethylation of erythromycin and hydroxylation of triazolam) and CYP3A content in rabbit hepatic microsomes preparations. The in vivo measures were oral clearance of triazolam and its formation clearance to its hydroxylated metabolites, alpha-hydroxytriazolam and 4-hydroxytriazolam. Rifampin increased CYP3A6 activity by 2- to 3-fold in hepatic microsomes compared to vehicle. Rifabutin increased CYP3A content 1.7-fold, but did not significantly increase microsomal CYP3A6 activity. Oral triazolam clearance and formation clearances to the two hydroxylated metabolites were 2- to 3-fold greater in rabbits treated with rifampin. These clearances were unaffected by rifabutin administration. Ex vivo enzyme activities correlated with in vivo changes in clearance of triazolam and the formation clearance to its hydroxylated metabolites. Rifabutin is a weaker inducer of CYP3A6 than rifampin. These data suggest that ex vivo enzyme activity is a viable approach to predict in vivo inductive potential of CYP3A inducers.

Animals↗
PubMed2001

The use of open MRI in otorhinolaryngology: initial experience.

Intraoperative imaging in head and neck surgery is a useful tool in many situations. In addition to being helpful for intraoperative orientation, real-time imaging enables visualization of the progress of surgery and the completeness of tumor resection. Regions in the head and neck to which access is difficult, and which therefore have a high incidence of morbidity and risk for the patient, can be approached more easily and safely in an open MRI than in a conventional way. Interventions in the open MRI (Signa SP, 0.5 Tesla) were performed with nonmagnetic instruments and an MR-safe microscope. For intraoperative navigation, the integrated FlashPoint system is helpful, because it allows targeting of the tumor by a calculated virtual line. T1W spin-echo, T2W fast spin-echo, and 3D T1W gradient-echo sequences were used for high-resolution imaging. Real-time imaging is achieved by fast multiplanar spoiled gradient-echo sequences or T2 single-shot fast spin-echo sequences. From 1996 to the present, we biopsied 17 petroclival tumors, performed paranasal sinus surgery in five cases, biopsied two neck masses, and inserted tubes for brachytherapy in 12 cases. No complications were observed. In all surgical procedures, a good resolution was obtained with MRI, especially for soft-tissue structures. The tumor could be targeted exactly, and all specimens revealed the relevant histology. In paranasal sinus surgery, however, the success rate was lower because it was difficult to distinguish blood from pathologic tissue. The insertion of tubes for brachytherapy was successful in all cases. It was possible to apply the tubes parallel to each other, 1 cm apart. Relevant biopsies could be taken of both neck masses. The indications for the use of open MRI in otorhinolaryngology are biopsies of tumors in regions that are difficult to approach, such as the petrous apex and petroclival region, the parapharyngeal space, and the orbit. Furthermore, the open MRI can be useful in paranasal sinus surgery, in the evaluation of tissue resection, and in the detection of the anatomy of delicate structures such as the internal carotid artery, the skull base, and the orbit. In addition, active navigation in the open MRI is possible with the integrated FlashPoint system. The advantage over conventional navigation systems lies in the possibility of real-time imaging, which allows detection of tissue changes occurring during the procedure.

Biopsy↗
PubMed2001

The elaboration of the 'Stockholm convention' on persistent organic pollutants (POPs): a negotiation process fraught with obstacles and opportunities.

The conclusion in December 2000 of the negotiations for the 'Stockholm Convention' can clearly be labeled as a success. The Convention text was negotiated in merely five sessions of the Intergovernmental Negotiating Committee (INC) and accomplished after its fifth session despite the fact that numerous controversial issues, such as the inclusion of new substances under the ambit of the Convention, the acknowledgement of the precautionary principle or--clearly most controversial--the financing mechanisms, remained to be resolved. This paper attempts to provide a somewhat impressionistic account of the negotiations leading to the conclusion of the 'Stockholm Convention' as experienced by the members of the Swiss delegation participating in the negotiations of the INC. Besides a brief overview on the 'history' of the negotiations, it will focus on some issues of special interest--and controversy--to the negotiators, and finally attempt to provide an outlook on the future of the work performed by the INC and the implementation of the Convention. Issues of special interest are environmental policy issues, capacity building and financing, trade-related issues, precautionary principles, and technical and scientific issues.

Commerce↗
PubMed2001

Injuries in mountain biking.

Despite still growing attraction mountain biking as a matter of sports traumatology still lacks relevant data based on large cross-sectional surveys. To obtain an overview of risk factors, types, and main body sites of injuries occurring in mountain biking we assessed the results of a questionnaire answered by 3873 athletes. A total of 8133 single lesions were reported by 3474 athletes, 36% of whom regularly participated in competitions. The incidence of injuries in mountain biking is comparable to that in other outdoor sports, the majority of injuries being minor. Mountain biking athletes were found to have an overall injury risk rate of 0.6% per year and 1 injury per 1000 h of biking. The main risk factors included slippery road surface, cyclist's poor judgement of the situation, and excessive speed, representing personal factors that could be altered by preventive measures. Of all injuries 14% were due to collision with some part of the bike, especially the pedals and the handlebar. While 75% of the injuries were minor, such as skin wounds and simple contusions, 10% were so severe that hospitalization was required. A breakdown of the injuries according to body site and frequency of occurrence is presented.

Adolescent↗